| Project/Area Number |
26670589
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
General surgery
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
宮澤 啓介 東京医科大学, 医学部, 主任教授 (50209897)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | オートファジー / 乳癌 / 小胞体ストレス / アグリソーム / プロテアソーム / アポトーシス / リソソーム / 微小管 / アグリゾーム |
|---|
| Outline of Final Research Achievements |
As ubiquitinated (Ub) proteins are concentrated at the aggresome upon proteasome failure, we focused on the microtubule as the scaffold of this transport pathway for aggresome formation. Treatment of metastatic breast cancer cell lines with a proteasome inhibitor bortezomib (BZ) resulted in induction of aggresome in a perinuclear lesion. Vinorelbine (VNR), which inhibits microtubule polymerization, more effectively suppressed BZ-induced aggresome formation than paclitaxel (PTX), which stabilizes microtubules. Combined treatment using BZ and VNR, but not PTX, enhanced apoptosis induction along with pronounced ER stress. The addition of azithromycin to block autophagy flux in the BZ plus VNR-containing cell culture further enhanced the cytotoxicity. These data suggest that suppression of BZ-induced aggresome formation using an inhibitory drug such as VNR for microtubule polymerization is a novel strategy for metastatic breast cancer therapy.
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